A number of central nervous system disorders such as anxiety, depression, motor disorders, etc., are believed to involve a disturbance of the neurotransmitter 5-hydroxytryptamine (5-HT) or serotonin. Serotonin is localized in the central and peripheral nervous systems and is known to affect many types of conditions including psychiatric disorders, motor activity, feeding behavior, sexual activity, and neuroendocrine regulation among others. The effects of serotonin are regulated by the various 5-HT receptor subtypes. Known 5-HT receptors include various 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7 subtypes.
The recently identified human 5-hydroxytryptamine-6 (5-HT6) receptor subtype has been cloned, and the extensive distribution of its mRNA has been reported. Highest levels of 5-HT6 receptor mRNA have been observed in the olfactory tubercle, the striatum, nucleus accumbens, dentate gyrus and CA1, CA2 and CA3 regions of the hippocampus. Northern blot analyses have revealed that 5-HT6 receptor mRNA appears to be exclusively present in the brain, with little evidence for its presence in peripheral tissues.
The high affinity of a number of antipsychotic agents for the 5-HT6 receptor, in addition to its mRNA localization in striatum, olfactory tubercle and nucleus accumbens suggests that some of the clinical actions of these compounds may be mediated through this receptor. Compounds which interact with, stimulate or inhibit the 5-HT6 receptor are commonly referred to as 5-HT6 ligands. These 5-HT6 receptor ligands are believed to be of potential use in the treatment of a variety of central nervous system disorders such as anxiety, depression, epilepsy, obsessive-compulsive disorders, migraine, cognitive disorders, sleep disorders, feeding disorders, attention deficit disorders, panic attacks, disorders relating to withdrawal from drug abuse, schizophrenia, or the like or in the treatment of certain gastrointestinal disorders such as irritable bowel syndrome.
Therefore, it is an object of this invention to provide compounds which are useful as therapeutic agents in the treatment of a variety of central nervous system disorders related to or affected by the 5-HT6 receptor.
It is another object of this invention to provide therapeutic methods and pharmaceutical compositions useful for the treatment of central nervous system disorders related to or affected by the 5-HT6 receptor.
It is a feature of this invention that the compounds provided may also be used to further study and elucidate the 5-HT6 receptor.
These and other objects and features of the invention will become more apparent by the detailed description set forth hereinbelow.
The present invention provides a compound of formula I 
wherein
Q is SO2, CO, CONR24, CSNR25 or CH2;
W is N or CR7;
X is N or CR9;
Y is NR or CR10R29;
Z is NR21 or CR11R30 with the proviso that when Y is NR then Z must be CR11R30 and with the further proviso that at least one of Y and Z must be NR or NR21;
n is 0 or an integer of 1 or 2;
R and R21 are each independently H, CNR26NR27R28, or a C1-C6alkyl, C3-C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
R1, R2 and R9 are each independently H, halogen, CN, OCO2R12, CO2R13, CONR22R23, CNR14NR15R16, SOmR17, NR18R19, OR20, or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6-cycloalkyl, cycloheteroalkyl, C1-C6alkanoyl, aryl or heteroaryl group each optionally substituted;
m is 0 or an integer of 1 or 2;
R3 and R4 are each independently H, halogen, C1-C4alkyl or C1-C4haloalkyl or R3 and R4 may be taken together with the atom to which they are attached to form a carbonyl group;
R5 and R6 are each independently H or an optionally substituted C1-C6alkyl group;
R7 is H, halogen, or a C1-C6alkyl, C1-C6alkoxy, aryl or heteroaryl group each optionally substituted;
R8 is an optionally substituted C1-C6alkyl, aryl or heteroaryl group;
R10, R11, R29 and R30 are each independently H or an optionally substituted C1-C6alkyl group;
R12, R13 and R17 are each independently H or an optionally substituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group;
R14 R15, R16, R18, R19, R26, R27 and R28 are each independently H or C1-C4alkyl;
R20, R22 and R23 are each independently H or an optionally substituted C1-C6alkyl group;
R24 and R25 are each independently H or an alkyl, aryl or heteroaryl group each optionally substituted; and
--- represents a single bond or a double bond; or
a pharmaceutically acceptable salt thereof.
The present invention further provides methods and compositions useful for the treatment of central nervous system disorders affected by or related to the 5-HT6 receptor.
The 5-hydroxytryptamine-6 (5-HT6) receptor is one of the most recent receptors to be identified by molecular cloning. Its ability to bind a wide range of therapeutic compounds used in psychiatry, coupled with its intriguing distribution in the brain has stimulated significant interest in new compounds which are capable of interacting with or affecting said receptor. At present, there are no known fully selective agonists. Significant efforts are being made to understand the possible role of the 5-HT6 receptor in psychiatry, cognitive dysfunction, motor function and control, memory, mood and the like. To that end, compounds which demonstrate a binding affinity for the 5-HT6 receptor are earnestly sought both as an aid in the study of the 5-HT6 receptor and as potential therapeutic agents in the treatment of central nervous system disorders.
Surprisingly, it has now been found that heterocyclylalkylindole or-azaindole compounds of formula I demonstrate affinity for the 5-HT6 receptor along with significant receptor sub-type selectivity. Advantageously, said formula I compounds are effective therapeutic agents for the treatment of central nervous system (CNS) disorders associated with or affected by the 5-HT6 receptor. Accordingly, the present invention provides heterocyclylalkylindole or -azaindole compounds of formula I 
wherein
Q is SO2, CO, CONR24, CSNR25 or CH2;
W is N or CR7;
X is N or CR9;
Y is NR or CR10R29;
Z is NR21 or CR11R30 with the proviso that when Y is NR then Z must be CR11R30 and with the further proviso that at least one of Y and Z must be NR or NR21;
n is 0 or an integer of 1 or 2;
R and R21 are each independently H, CNR26NR27R28, or a C1-C6alkyl, C3-C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
R1, R2 and R9 are each independently H, halogen, CN, OCO2R12CO2R13, CONR22R23, CNR14NR15R16, SOmR17, NR18R19, OR20, or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6-cycloalkyl, cycloheteroalkyl, C1-C6alkanoyl, aryl or heteroaryl group each optionally substituted;
m is 0 or an integer of 1 or 2;
R3 and R4 are each independently H, halogen, C1-C4alkyl or C1-C4haloalkyl or R3 and R4 may be taken together with the atom to which they are attached to form a carbonyl group;
R5 and R6 are each independently H or an optionally substituted C1-C6alkyl group;
R7 is H, halogen, or a C1-C6alkyl, C1-C6alkoxy, aryl or heteroaryl group each optionally substituted;
R8 is an optionally substituted C1-C6alkyl, aryl or heteroaryl group;
R10, R11, R29 and R30 are each independently H or an optionally substituted C1-C6alkyl group;
R12, R13 and R17 are each independently H or an optionally substituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group;
R14, R15, R16, R18, R19, R26, R27 and R28 are each independently H or C1-C4alkyl;
R20, R22 and R23 are each independently H or an optionally substituted C1-C6alkyl group;
R24 and R25 are each independently H or an alkyl, aryl or heteroaryl group each optionally substituted; and
--- represents a single bond or a double bond; or
a pharmaceutically acceptable salt thereof.
As used in the specification and claims, the term halogen designates Br, Cl, I or F; the term aryl designates phenyl or naphthyl; and the term cycloheteroalkyl designates a 5- to 7-membered monocyclic ring system containing 1 or 2 heteroatoms, which may be the same or different, selected from N, O or S and optionally containing one double bond. Exemplary of the cycloheteroalkyl ring systems included in the term as designated herein are the following rings wherein Y is NR, O or S. 
Similarly, as used in the specification and claims, the term heteroaryl designates a 5- to 10-membered monocyclic or bicyclic aromatic ring system containing 1 or 2 heteroatoms, which may be the same or different, selected from N, O or S. Such heteroaryl ring systems include pyrrolyl, azolyl, oxazolyl, thiazolyl, imidazolyl, furyl, thienyl, quinolinyl, isoquinolinyl, indolinyl, benzothienyl, benzofuranyl, benzisoxazolyl and the like. The term haloalkyl designates a CnH2n+1 group having from one to 2n+1 halogen atoms which may be the same or different; and the term haloalkoxy designates an OCnH2n+1 group having from one to 2n+1 halogen atoms which may be the same or different.
In the specification and claims, when the terms C1-C6alkyl, C2-C6alkenyl, C2-C6alkynl, C3-C7-cycloalkyl, cycloheteroalkyl, C1-C6-alkanoyl, aryl or heteroaryl are designated as being optionally substituted, the substituent groups which are optionally present may be one or more of those customarily employed in the development of pharmaceutical compounds or the modification of such compounds to influence their structure/activity, persistence, absorption, stability or other beneficial property. Specific examples of such substituents include halogen atoms, nitro, cyano, thiocyanato, cyanato, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, formyl, alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, alkylsuphinyl, alkylsulphonyl, carbamoyl, alkylamido, phenyl, phenoxy, benzyl, benzyloxy, heterocyclyl or cycloalkyl groups, preferably halogen atoms or lower alkyl groups. Typically, up to 3 substituents may be present. When any of the foregoing substituents represents or contains an alkyl substituent group, this may be linear or branched and may contain up to 12, preferably up to 6, more preferably up to 4 carbon atoms.
Pharmaceutically acceptable salts may be any acid addition salt formed by a compound of formula I and a pharmaceutically acceptable acid such as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, mandelic, malonic, succinic, fumaric, acetic, lactic, nitric, sulfonic, p-toluene sulfonic, methane sulfonic acid or the like.
Preferred compounds of the invention are those compounds of formula I wherein n is 1. Also preferred are those compounds of formula I wherein R3 and R4 are H. Further preferred compounds of the invention are those compounds of formula I wherein Q is SO2 or CO. Another preferred group of formula I compounds are those compounds wherein --- represents a single bond.
More preferred compounds of the invention are those compounds of formula I wherein Q is SO2; X is CR9; Y is CR10R29; Z is NR21; and R3 and R4 are H. Another group of more preferred inventive compounds are those formula I compounds wherein Q is SO2; X is CR9; Y is CR10R29; Z is NH; R3 and R4 are H; R8 is an optionally substituted aryl group; and ---  represents a single bond.
Among the preferred compounds of the invention are:
5-fluoro-1-(phenylsulfonyl)-3-(piperidin-4-ylmethyl)-1H-indole;
5-fluoro-1-(phenylsulfonyl)-3-(1,2,5,6-tetrahydro-3-pyridinylmethyl)-1H-indole;
4-{[5-fluoro-3-(4-piperidinylmethyl)-1H-indol-1-yl]sulfonyl}aniline;
1-[(2,6-dichlorophenyl)sulfonyl]-5-fluoro-3-(4-piperidinylmethyl)-1H-indole;
1-[(3,4-dichloro-2-thienyl)sulfonyl]-5-fluoro-3-(4-piperidinylmethyl)-1H-indole;
5-fluoro-1-(1-naphthylsulfonyl)-3-(4-piperidinylmethyl)-1H-indole;
1-[(3,4-dimethoxyphenyl)sulfonyl]-5-fluoro-3-(piperidin-4-ylmethyl)-1H-indole;
4-{[5-fluoro-3-(piperidin-4-ylmethyl)-1H-indol-1-yl]sulfonyl}benzonitrile;
8-{[5-fluoro-3-(piperidin-4-ylmethyl)-1H-indol-1-yl]sulfonyl}quinoline;
1-(phenylsulfonyl)-3-(piperidin-4-ylmethyl)-1H-indole;
1-(1-naphthylsulfonyl)-3-(piperidin-4-ylmethyl)-1H-indole;
4-{[3-(piperidin-4-ylmethyl)-1H-indol-1-yl]sulfonyl}phenylamine;
1-[(3,4-dichlorothien-2-yl)sulfonyl]-3-(piperidin-4-ylmethyl)-1H-indole;
1-(phenylsulfonyl)-3-(piperidin-4-ylmethyl)-1H-pyrrolo[2,3-b]pyridine;
1-(1-naphthylsulfonyl)-3-(piperidin-4-ylmethyl)-1H-pyrrolo[2,3-b]pyridine;
4-{[3-(piperidin-4-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl]sulfonyl}phenylamine;
1-[(3,4-dichlorothien-2-yl)sulfonyl]-3-(piperidin-4-ylmethyl)-1H-pyrrolo[2,3-b]pyridine;
6-flouro-1-(phenylsulfonyl)-3-(4-piperidinylmethyl)-1H-indole;
6-flouro-1-(1-naphthylsulfonyl)-3-(4-piperidinylmethyl)-1H-indole;
6-flouro-1-(3,4-dimethoxyphenylsulfonyl)-3-(4-piperidinylmethyl)-1H-indole;
6-flouro-1-(2-chlorophenylsulfonyl)-3-(4-piperidinylmethyl)-1H-indole;
6-flouro-1-(5-chlorothien-2-ylsulfonyl)-3-(4-piperidinylmethyl)-1H-indole;
6-flouro-1-(2-fluorophenylsulfonyl)-3-(4-piperidinylmethyl)-1H-indole;
6-flouro-1-(3-fluorophenylsulfonyl)-3-(4-piperidinylmethyl)-1H-indole; and
the pharmaceutically acceptable salts thereof.
Compounds of the invention may be prepared using conventional synthetic methods and, if required, standard separation or isolation techniques. For example, compounds of formula I wherein Q is SO2; W is CR7; Y is CH2; Z is NH; n is 1; --- represents a single bond; and R3 and R4 are H (Ia) may be prepared by reacting a compound of formula II with 4-pyridinecarboxaldehyde to give the corresponding hydroxymethylpyridine of formula III. Said formula III compound may be fully reduced to give the piperidinyl-methyl compound of formula IV. Said formula IV compound may be protected with a group such as t-butyl carbonate (Boc) to give the protected compound of formula V and the protected compound may then be sulfonated using the appropriate sulfonyl halide reagent and deprotected to give the desired formula Ia compound. The reaction sequence is shown in flow diagram I. 
Compounds of formula I wherein --- represents a double bond; Q is SO2; Y is NH; Z is CH2; n is 1; and R3 and R4 are H(Ib) may be prepared by reacting the formula II substrate with 3-pyridine carboxaldehyde to form the corresponding hydroxymethylpyridine compound of formula VI; partially reducing said formula VI compound to give the indolyl- or azaindolylmethylpyridine of formula VII; reacting said formula VII pyridine with benzylbromide to form the pyridinium bromide of formula VIII, reacting the formula VIII pyridinium salt with NaBH4 to give the tetrahydro-3-pyridinylmethyl compound of formula IX; debenzylating said formula IX compound with chloroethylchloroformate to give the compound of formula X; and then sequentially protecting, sulfonating and deprotecting said formula X compound as described hereinabove to give the desired formula Ib compound. The reaction sequence is shown in flow diagram II, wherein G represents a protecting group and xcfx86 represents a phenyl group. 
Compounds of formula I wherein R and R21 are other than hydrogen may be prepared by alkylating a compound of formula Ia or Ib with an appropriate alkylating agent such as an alkyl halide. Compounds of formula I wherein Q is CO, CONR24 or CH2 may be prepared by reacting a protected compound of formula V or formula IX with a carbonyl halide, carbamoyl halide or alkyl halide respectively. Employing these and other literature procedures, the formula I compounds of the invention may be prepared.
Advantageously, the inventive compound of formula I may be utilized in the treatment of central nervous system disorders relating to or affected by the 5-HT6 receptor such as motor, mood, psychiatric, cognitive, neurodegenerative, or the like disorders. In particular, CNS disorders such as anxiety, depression, schizophrenia, Alzheimer""s disease, Parkinson""s disease, eating disorders, disorders related to alcohol or drug withdrawal, sexual dysfunction, attention deficit disorder, memory loss or the like. Accordingly, the present invention provides a method for the treatment of a disorder of the central nervous system (CNS) related to or affected by the 5-HT6 receptor in a patient in need thereof which comprises providing said patient with a therapeutically effective amount of a compound of formula I as described hereinabove. The compounds may be provided via oral or parenteral administration or in any common manner known to be an effective administration of a therapeutic agent to a patient in need thereof.
The therapeutically effective amount provided in the treatment of a specific CNS disorder may vary according to the specific condition(s) being treated, the size, age and response pattern of the patient, the severity of the disorder, the judgment of the attending physician and the like. In general, effective amounts for daily oral administration may be about 0.01 to 1,000 mg/kg, preferably about 0.5 to 500 mg/kg and effective amounts for parenteral administration may be about 0.1 to 100 mg/kg, preferably about 0.5 to 50 mg/kg.
In actual practice, the compounds of the invention are administered in a solid or liquid form, either neat or in combination with one or more conventional pharmaceutical carriers or excipients. Accordingly, the present invention provides a pharmaceutical composition which comprises a pharmaceutically acceptable carrier and an effective amount of a compound of formula I as described hereinabove.
Solid carriers suitable for use in the composition of the invention include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aides, binders, tablet-disintegrating agents or encapsulating materials. In powders, the carrier may be a finely divided solid which is in admixture with a finely divided compound of formula I. In tablets, the formula I compound may be mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. Said powders and tablets may contain up to 99% by weight of the formula I compound. Solid carriers suitable for use in the composition of the invention include calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
Any pharmaceutically acceptable liquid carrier suitable for preparing solutions, suspensions, emulsions, syrups and elixirs may be employed in the composition of the invention. Compounds of formula I may be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, or a pharmaceutically acceptable oil or fat, or a mixture thereof. Said liquid composition may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, coloring agents, viscosity regulators, stabilizers, osmo-regulators, or the like. Examples of liquid carriers suitable for oral and parenteral administration include water (particularly containing additives as above, e.g., cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) or their derivatives, or oils (e.g., fractionated coconut oil and arachis oil). For parenteral administration the carrier may also be an oily ester such as ethyl oleate or isopropyl myristate.
Compositions of the invention which are sterile solutions or suspensions are suitable for intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions may also be administered intravenously. Inventive compositions suitable for oral administration may be in either liquid or solid composition form.
For a more clear understanding, and in order to illustrate the invention more clearly, specific examples thereof are set forth hereinbelow. The following examples are merely illustrative and are not to be understood as limiting the scope and underlying principles of the invention in any way.
Unless otherwise stated, all parts are parts by weight. The terms HPLC and NMR designate high performance liquid chromatography and nuclear magnetic resonance, respectively.